According to UN AIDS, 50% of the approximately 40 Million HIV-1 infected individuals worldwide are women, and the majority of HIV-positive women is of childbearing age and become infected through heterosexual intercourse. Studies comparing the course of HIV-1 infection and disease between women and men have demonstrated significant gender differences in HIV-1 pathogenesis. Overall, HIV-1-infected women tend to have lower viral load levels early in HIV-1 infection. However, proportional-hazards models in studies by Drs. Quinn and Vlahov showed that women with the same viral load as men had a 1.6-fold higher risk of AIDS (95% CI=1.10-2.32); or, equivalently, that women with half the viral load of men had a similar time to AIDS as men. The mechanisms underlying these significant differences in HIV-1 pathogenesis between women and men are not fully understood. It is well established that women and men differ in their responses to viral infections and vaccination, and that sex hormones play an important role in modulating antiviral immunity. In a study recently published in Nature Medicine, we showed that HIV-1-infected women exhibit significantly higher levels of CD8+ T cell activation than men for the same viral load, and that pDCs from women produce significantly higher amounts of pro-inflammatory cytokines than pDCs from men in response to HIV-1 encoded TLR7 ligands. These novel data suggest that difference in HIV-1 pathogenesis between women and men are in part due to differences in the ability of Toll-like receptors (TLRs) to sense components of HIV-1 and to mediate activation of the immune system. Here we propose to build on these initial findings, and (i) to assess the impact of sex hormones on TLR signaling to identify the pathways responsible for the observed differences between women and men; (ii) to study the direct consequences of sex differences in the TLR-mediated pDC activation and IFN- 1 on T cell activation; and (iii) to explore the potential of targeting the TLR pathway therapeutically to reduce HIV-1-induced immune activation and immunopathology in BLT mice. These proposed studies will contribute significantly to our understanding of the mechanisms leading to immune activation in HIV-1 infection, and their consequences for HIV-1 pathogenesis, using the sex differences in TLR7/8-mediated IFN-a production we recently described as a tool. The use of a TLR antagonist in the humanized BLT mouse model of HIV-1 infection will furthermore allow us to directly modulate this pathway, and to determine whether TLR7/8 stimulation by HIV-1 is a causal mechanism for inducing HIV-1 associated immune activation. The results from these studies will guide future translation studies in humans, and might provide rational to use TLR antagonists to reduce HIV-1-induced immune activation and consecutive pathology. PUBLIC HEALTH RELEVANCE: According to UNAIDS, 50% of the approximately 40 Million HIV-1 infected individuals worldwide are women. Studies comparing the course of HIV-1 infection and disease between women and men have demonstrated significant gender differences in HIV-1 pathogenesis. The mechanisms underlying these differences in HIV-1 pathogenesis between women and men are not fully understood, but novel data have demonstrated significant gender differences in the ability of pDCs to sense HIV-1 through Toll-like receptor (TRL) 7 and to mediate activation of the immune system. Here we propose to study the direct consequences of these sex differences in the TLR-mediated pDC activation on HIV-1 immunity, to assess the impact of sex hormones on TLR7 signaling and to explore the potential of targeting this pathway therapeutically to reduce HIV-1-induced immune activation and immunopathology.